DRUG-DRUG INTERACTIONS IN CV PATIENTS

CLINICAL PHARMACY

OCCURRENCE OF DRUG-DRUG

INTERACTIONS IN CARDIOVASCULAR PATIENTS

ABSTRACT

Background: Drug-drug interaction is defined as the effect of one drug is altered in the presence of other drug. It may be pharmacokinetic or pharmacodynamics. Cardiovascular diseases are the most occurring diseases in Pakistan and world-wide. As there is increase rate of death and a lot of drugs are prescribed to this group, there is increase chance of drug-drug interactions in these patients. These drug-drug interactions may be fatal and life-threatening to some patients especially elderly.

Method & Result: The observational prospective study was carried out for 40 patients at community level. While evaluating their prescriptions it was found that 20 out of 40 patients (50%) have drug-drug interactions. 45% patient had heart disease because of family history. Those included 9 (45%) males and 11 females (55%). Males less in number had large number of drug-drug interactions, may be due to large numbers of drugs prescribed in this group. Patients less than 50 years age had 5 major type interactions, whileelder people had increase number of moderate type interactions.Out of 20 patients with interactions 15 (75%) had comorbidities, with 11 (55%) patients having diabetes.

Conclusion: The major drug class interacting with cardiovascular drug class was anti-diabetic drugs. It was found that the most interacting drugs are aspirin and clopidogrel, clopidogrel and atorvastatin, clopidogrel and omeprazole, atenolol and aspirin, aspirin and perindopril and many others.

INTRODUCTION

DRUG-DRUG INTERACTIONS

The increase number of drugs prescribed in combination result in the increase incidence of drug-drug interactions. Drug-drug interactions can be defined as the phenomenon that occurs when the effects or pharmacokinetics of a drug are altered by prior administration or co administration of a second drug”(Tatro 2011:xvii).

The occurrence of adverse reactions as result of interactions is not known. Patient is monitored for interactions on the basis of changes caused by interactions such as serum drug concentration, amount of drug excreted or other laboratory values. Most drug interactions are avoided by simple monitoring or adjustment of dose while other need to stop or chage the combination(Tatro 2011:xxvi).

TYPES OF DRUG INTERACTION

The drug-drug interactions are classified as pharmacokinetic or pharmacodymamic.

·         Pharmacokinetic interactions are those in which one drug alter the pharmacokinetic of other drug.

·         Pharmacodynamic interactions are those in which one drug results in the alteration on patient response in the presence of other drug. This is usually measured by change in the laboratory values(Tatro 2011:xvii).

INCIDENCE AND SEVERITY OF DRUG INTERACTIONS

The incidence and severity of drug interaction depends on the patient characteristics and information about dose and use of drug(Tatro 2011:xii).The severity of drug interactions is important for knowing the risk and benefit of therapy. The degrees of severity are:

·         Majorinteractions are life-threatening and require to use alternative therapy.

·         Moderate interactions are also severe and cause change in the patient examination. Hospitalization may be required. Dose adjustment is first step to mange moderate interactions.

·         Minor interactions are mild and need no special precautions.

The incidence of interaction is presented by

• ·             Major
• ·             Moderate
• ·             Minor
• ·            Major/ Moderate
• ·             Minor/any other

The incidence of interaction tells not only about the incidence but also the severity of interactions

(Tatro 2011:xiv).

CARDIOVASCULAR DISEASES

The cardiovascular system comprises the heart and blood vessels, and responsible for transport of oxygen and nutrients to organs of body. The cardiovascular disorders are most common diseases in the world nowadays.The incidence of cardiovascular diseases has increased. Cardiovascular diseases are major cause of death worldwide. In Pakistan for year 2008 estimated death by cardiovascular diseases is 400 deaths per 100000 populations(OECD/WHO 2012).

Patients with cardiovascular diseases are more vulnerable to drug-drug interactions due to aging, gender and co morbidities especially diabetes and also because of large number of drugs prescribed to single patient. With increase risk or potential of diabetes with CV diseases, there are more observed interactions between the cardiac and antihyperglycemic agent.

Cardiovascular Risk factors   according to JNC7 20

1. ·         Hypertension
2. ·         Age (older than 55 years for men, 65 years for women)
3. ·         Diabetes mellitus
4. ·         Elevated LDL (or total) cholesterol, or low HDL cholesterol
5. ·         Estimated GFR <60 mL/min
6. ·         Family history of premature CVD (men <55 years of age orwomen <65 years of age)
7. ·         Obesity
8. ·         Physical inactivity
9. ·         Tobacco usage, particularly cigarettes

Important Cardiovascular Diseases

The cardiovascular diseases have been progressing widely effecting large number of people. Previously these are diseases of elderly with little number of adult carrying it. Nowadays these are also well known diseases in the adult population. The cardiovascular diseases are

• ·         Hypertension
• ·         Ischemic Heart Disease
• ·         Myocardial Infarction
• ·         Angina
• ·         Congestive Heart Failure
• ·         Stroke
• ·         Atheriosclerosis
• ·         Arrhythmia, etc

TREATMENT OF CARDIOVASCULAR DISEASES

Treatment of Cardiovascular diseases are classified into non-pharmacological and pharmacological.

Non-Pharmacological includes Lifestyle modification required for prevention from Cardiovasular disease..

•Encourage healthy lifestyles for all individuals.

Table 1: Lifestyle modification of prevention from Cardiovascular diseases (Chobanian 2004:26)

Lifestyle Modifications	Reccommendation
Weightreduction	Maintain normal body weight (BMI 18.5–24.9kg/m2).
DASH eatingplan	Adopt a diet rich in fruits,vegetables, and lowfat dairyproducts with reduced contentof saturated and total fat.
DietarySodiumreduction	Reduce dietary sodium intake to2.4 g sodiumor 6 g sodium chloride per day.
Alcoholconsumption	Men: limit to <2 drinks per day. Women and lighter weight persons: limit to <1 drink per day
Aerobic exercise	Regular aerobic physical activity (e.g., walking) at least30 minutes per day, most daysof the week.

Pharmacological treatment includes important drugs belong to different classes having some common or different interactions..

Table 2: Drugs used in Cardiovascular diseases (Dyker 2012:304)

Drug	Therapeutic Use
ACE Inhibitor	Hypertension Heart Failure Post-myocardial infarction Diabetic nephropathy Left ventricular dysfunction
β-blockers	Hypertension Angina Heart Failure (stable) Post-myocardial infarction Atrial fibrillation Pregnancy
Calcium antagonists Nifedipine                       Amlodipine                       Verapamil Diltiazem	Systolic Hypertension in the elderly Angina Pregnancy Black patients Hypertension Angina Atrial fibrillation

Diuretics	Systolic Hypertension in the elderly Heart Failure Black patients
Aldosterone antagonist	Heart Failure Post-myocardial infarction Conn’s Syndrome
Angiotensin receptor blockers	Hypertension Heart Failure
Nitrates	Angina Myocardial Infarction
Cardiac Glycosides	Chronic Symptomatic Heart Failure Atrial Fibrillation
α-blockers	Hypertension Benign prostatic hyperplasia
Statins	Acute coronary disease Atherosclerosis
Antiplatelets	Myocardial Infarction Angina

SOME CARDIOVASCULAR DISEASES

1.      HYPERTENSION

Hypertension can be defined as the condition in which blood pressure is elevated to extent that benefit is obtained by blood pressure lowering (Dyker 2012:295).Blood Pressure is the force of blood exerted on the vessel walls. Blood pressure is measured in the form of systolic B.P/diastolic B.P. Systolic B.P is pressure of blood during contraction phase of heart while diastolic B.P is pressure of blood during relaxation phase of heart(Patil& Singh 2009:169). Normal blood pressure is less than 120/80. Blood pressure 140/90 and above should be treated.

Before measuring blood pressure patient should be relaxed and resting. Blood pressure is measured in both limbs and both sitting and standing positions. High value is considered for treatment(Nasir&Inayatullah 2010:135).

Types of Hypertension

According to JNC-7 guideline_____

·         Normal                                                <120/80           mmHg

·         Prehypertensive                                   120-139/80-89 mmHg

·         Hypertensive Stage 1                          140-159/90-99 mmHg

·         Hypertensive Stage 2                          ≥160/100         mmHg

Management of Hypertension:

Table 3: Management of different type of Hypertension(Dyker 2012:299)

Initial Blood Pressure	Management
Malignant	Admit and treat immediately
>220/120	Check several time and treat immediately if B.P lie in this range
180-219/110-119	Check for 1-2 weeks, and treat if lie in this range
160-179/100-109	Check for 3-4 week(end organ damage) and 2-12 weeks(no end organ damage) with non-pharmacological approaches. Treat if blood pressure remain in this range.
140-159/90-99	Check for several weeks with with non-pharmacological approaches. Treat in case of end organ damage.
135-139/85-89	Annually check.
<135/85	Check in 5 years

Treatment of Hypertension

The main groups of drugs in treatment of hypertension are ACE inhibitors, Beta-blockers, Calcium-channel blocker, diuretics, spironolactone and Alpha-blockers (Table 4).

Table 4: Drugs used in Hypertension (Dyker 2012:303)

Drug Class	Important Drugs
ACE inhibitors	Captopril Perindopril Lisinopril Ramipril
Calcium Channel blockers	Nifedipine Amlodipine Verapamil Diltiazem
Diuretics	Furosemide Hydrochlorothiazide Spironolactone
β-blockers	Atenolol Propanalol Metoprolol Carvedilol
α-blockers	Parazosin Terazosin
Angiotensin receptor blockers	Losartan Valsartan

ALOGRITHM FOR TREATMENT OF HYPERTENSION

·         NICE Algorithm for Treatment of Hypertension

Figure 1: NICE Alogrithm for treatment of Hypertension

                      JNC Alogrithm for treatment of hypertension

Figure . Algorithm for treatment of hypertension (Chobanion 2004:31)

1.      ISCHAEMIC HEART DISEASE

Ischaemic heart Disease (IHD) also called as coronary heart disease (CHD) or coronary artery disease (CAD) is a condition in which vascular supply to artery is blocked by atheroma (artery wall swelling), thrombosis or arterial spasm. This may result in impaired supply of blood to cardiac tissue (McRobbie 2012:312). Coronary artery disease affects the arteries. Narrowing of coronary arteries (arteries supply to myocardium) result in ischaemia (Patil&Singh 2009:173).

Angina and Chest pain is most common symptom.

2.      ANGINA PECTORIS

Angina pectoris is defined as chest pain cause by disruption in balance and demand for oxygen by the heart thus result in lack of oxygen to myocardium (Patil& Singh 2009: 181).

Treatment of Angina

Table 5: Drugs used in Angina (McRobbie 2012:315-320)

Drug class		Important drugs
Antithrombotic		Aspirin Clopidogrel
ACE inhibitors		Ramipril
Statins	Atorvastatins
For symptoms relief and prevention
β-blockers		Atenolol Bisoprolol Metoprolol
Calcium channel blockers		Verapamil Diltiazem Nefidipine
Nitrates		Nitroglycerin (GTN) Isosorbidedinitrate Isosorbidemononitrate
Others		Nicorandil Ranolazine

3.      MYOCARDIAL INFARCTION

Interruption in blood supply to myocardium is referred as myocardial infarction (MI). The main site of MI is left ventricle. Symptoms include:

• ·         Chest pain
• ·         Pain radiating down the left arm
• ·         Pain radiating to jaw and neck
• ·         Pain followed by SOB (shortness of breath), dizziness, NV (nausea and vomiting)
• ·         Increased heart rate, decreased B.P, increased temperature and increased respiratory rate(Patil& Singh 2009: 182).

Table 6:Drugs used in MI (McRobbie 2012:319-322)

Drug class	Important Drug
Antiplatelet	Aspirin Clopidogrel
Anticoagulant	Heparin
Nitrate	GTN

4.      CHRONIC HEART FAILURE

      Heart failure (HF) results when cardiac output is not enough to supply oxygen needed by body organ. The common causes are CAD and hypertension (Katzung&Parmley 2009:209). Most common symptoms are shortness of breath, fatigue and ankle swelling.

New York Heart Association (NYHA) classified patients of Heart failure in four groups according to their conditions.

Table7: NYHA classification of chronic Heart Failure patients (Hudson &McAnaw&Dreischulte 2012:333)

Asymptomatic	I	No symptoms with slight physically active (walking and climbing stairs)
Symptomatic	II	Slight limitation with dyspnoea on moderate to severe activity like climbing stairs
	III	Marked limitation of physical activity, less than ordinary activities cause dyspnoea
	IV	Disable, dyspnoea at rest

Treatment of Heart Failure

Table 8: Drugs used in Heart Failure (Hudson &McAnaw&Dreischulte 2012:339-342)

Drug Class	Important Drugs
Diuretics	Furosemide Bendroflumethiazide
Aldosterone Antagonist	Spironolactone
ACE Inhibitors	Captopril Ramipril Lisinopril
β-blockers	Carvedilol Bisoprolol Metoprolol Nebivolol
Nitates	GTN Isosorbidemononitrate Isosorbidedinitrate
Angiotensin receptor blockers	Losartan Valsartan
Cardiac Glycosides	Digoxin
Vasodilators	Hydralazine

5.      ARRHYTHMIA

Arrhythmia is the abnormality in heartbeat. The heart beat may be above or below the normal limit resulting in trachycardia and bradycardia respectively.

·         Trachycardia:heartbeat greater than 100 beats per min.

·         Bradycardia: heartbeat less than 60 beat per min (Nasir&Inayatullah 2010:235).

Treatment of Arrhythmia

Arrhythmia should be treated as soon as possible because abnormality in heart rhythm may lead to many different conditions.  Drugs used to treat arrhythmia, i.e. antiarrhythmic drugs are divided into four classes as:

Table 9: Drugs used in Arrhythmia (Hume & Grant 2009:246-247;Sporton& Antoniou 2012:367).

Drug Class	Important Drugs
Class I	Procainamide Lidocaine Moricizine Phenytoin
Class II	β-blockers
Class III	Amiodarone Bretyliumtosylate
Class IV	Calcium channel blockers

         MAJOR DRUG CLASSES USED IN CARDIOVASCULAR DISEASES AND IMPORTANT INTERACTIONS

Table 10: Drug interactions of Cardiovascular Drugs and their Management (Hudson &McAnaw&Dreischulte2012:348 ;Tatro 2011)

Drug	Interacts with	Possible danger	Management
Diuretics	NSAIDs	Decreased diuretic effect and increased risk of renal impairment	Consider other inflammatory agents
	Lithium	Lithium toxicity	Monitor lithium level and adjust dose
ACE inhibitors/ ARB	NSAIDS	Hypotensive effect reduced. Increased riskof renal impairment	Monitor B.P
	Lithium	Lithium toxicity	Monitor lithium level and use alternative antihypertensive therapy
	Diuretic	Effect of diuretic decreased	fluid status and body weight should be monitored
β-blockers	Amiodarone	Increased risk of bradycardia	No special precaution
	Diltiazem	Increased risk of AV block &bradycardia	Decrease dose or alternative therapy
	Verapamil	Increased risk of hypotension and heart failure	Monitor cardiac function, reduce dose
Spironolactone	Digoxin	Interfere with measurement of digoxin resulting in false measurement	Monitor digoxin dose
Digoxin	Amiodarone	Digoxin toxicity	Reduce digoxin dose
	Quinidine	Digoxin toxicity	Reduce digoxin dose 50%
	Verapamil	Increased risk of AV block	Decrease digoxin dose
	Diuretic	Increased risk of hypokalaemia and toxicity	Monitor Potassium and magnesium level
Nitrates	Sildenafil	Severe hypotensive effect	Combination is contraindicated

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      METHOD

      STUDY DESIGN, POPULATION AND DATA COLLECTION

    A prospective observational study was carried out in the general public area. Patients who have any cardiac disease were included in the study. The study population comprised of the patients aged 40 year or older. Data regarding demographic information (age, weight, gender and education), main diagnosis, comorbidities, prescribed medications, OTC medications, homeopathic, herbal medications, laboratory investigations and diet plan were obtained from clinical records and patient interviews.

All individualized prescriptions (including OTC medications) were screened for drug-drug interactions by using Drug Interaction Facts 2012™ (Tatro 2011). Certain demographic characteristics such as patient age, gender, family history and comorbidities were studied to find out number and strength of interaction. The interactions observed were classified as Major, Moderate and Minor according to level of significance obtained from Drug Interaction Facts 2012™.

             

    RESULT

     A total of 40 prescriptions were analyzed during study period and it was found that 20 patients were confirmed with minimum of one drug-drug interaction (50%).

      FAMILY HISTORY

     Out of 40 patients, 18 patients (45%) had family history of heart disease.

   T                                                 AGE GROUP      Table 1: Occurrence of drug-drug interactions in specific age group

	Age <50 years	Age 50-60 years	Age >60 years
Total interactions	18	18	14
MAJOR	5	1	1
MODERATE	5	10	10
MINOR	8	7	3

             The age group less than 50years had 18 interactions, classified as major-5, moderate-5 and minor-8. The age group from 50 to 60 years had 18 interactions, classified as major-1, moderate-10 and minor-7. The age group more than 60 years had 14 interactions, classified as major-1, moderate-10 and minor-3.

         GENDER    

   The proportion of patient with drug-drug interactions was females numbering 11(55%) and males numbering 9(45%).The males, slightly less than females, had more number of interactions (24 interactions) as compared to females (20 interactions). That may be due to large number of drugs taken by males as compared to females.     

                               

                                Table 2: No. of Patients having interactions

Patient Characteristics	No. of Patients having interactions	% of Patients having interactions
Gender Group        Male        Female	9 11	45% 55%

    

     COMORBIDITIES                             Out of 20 patients 15 had comorbidities, most common being diabetes. All 15 patients had 36 interactions (75%).

            Table 3: Patients with or without comorbidities

Comorbidities	No. of Patients with interactions	% of Patients with interactions
Diabetes	11	55%
Other comorbidities	4	20%
No comorbidities	5	25%

·    

     Antihyperglycaemic drugs are the most important drugs involved in interaction after cardiac drugs. Diabetes were most common commorbidities (55% of study group) thus a large number of anti-hyperglycaemic drugs involved in interactions.

·         OTC products were also involved in interactions.

     COMMON DRUG-DRUG INTERACTIONS:

               Table 4: Common Drug-drug interaction observed in the data

MAJOR Aspirin↔clopidogrel Spironolactone↔lisinopril Clopidogrel↔Omeprazole

MODERATE Atorvastatin↔clopidogrel Atenolol↔aspirin Aspirin↔Bisoprolol Aspirin↔lisinopril Aspirin↔metoprolol Aspirin↔ramipril Aspirin↔Captopril Aspirin↔perindopril Glyburide↔Captopril Diltiazem↔Ranitidine

MINOR Furosemide↔acetaminophen Aspirin↔furosemide Spironolactone↔aspirin Lisinopril↔furosemide Furosemide↔Glimepiride Aspirin↔Omeprazole

   DISCUSSION

      According to this study overall incidence of drug-drug interactions in community was 50%. This study showed that the incidence of drug-drug interactions is associated with age, gender, number of drugs in prescription and comorbidities. 

      Drug-drug interaction is basically depending on the number of drugs prescribed and used by patients. As the number of drugs increases the possibility of drug-drug interactions also increase.

      The results showed the high incidence of MAJOR interactions in the patients aged lower than 50 years and high incidence of MODERATE interactions were seen in patients aged 50 years or elderly. In elderly due to disease and aging, renal elimination and liver metabolism of drugs may be impaired resulting in potential drug–drug interactions. Thus in elderly MODERATE-type interactions have special importance for monitoring as they may be life-threatening in these patients. The MILD interactions are of less important and a lot of minor interactions were found there.

   The most important drug classes involved in drug interactions were anti-platelets (aspirin and clopidogrel), ACE inhibitors (captopril, perindopril, etc), β-blockers (atenolol, carvedilol, etc) and anti-hyperglycemic (sulfonylureas). Among these drug classes, aspirin and clopidogrel, clopidogrel and atorvastatin, clopidogrel and omeprazole, atenolol and aspirin, aspirin and perindopril etc were the most important interactions. These interactions were classified as major, moderate or minor on the basis of its level of significance. The incidence of interactions belong to commonmost interactions are shown in the following figure (Fig1).

  ROLE OF PHARMACIST IN MANAGING DRUG-DRUG INTERACTIONS IN CARDIOVASCULAR PATIENTS

     The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the drugs and their cause of use and the risk of side effects associated with it. With their detailed knowledge of medicine, pharmacists have ability to manage drug-drug interactions in hospital or at community level. In Pakistan pharmacist duty is not fully recognized. First public and especially physician should be aware of pharmacist duty. Pharmacists perform following role in managing drug-drug interactions.

·         Check possible drug interactions before dispensing.

·         In case of any possible drug interactions tell doctor about the interactions and how to overcome it.

·         Monitoring and evaluating the patient’s response to therapy, including safety and effectiveness

·         Providing verbal education and training designed to enhance patient understanding and appropriate use of his or her medications.

·         Give health care practitioners a complete list of all of commonly used drugs and their important interactions.

·         Inform health care practitioners when medications are added or discontinued.

·         Since the frequency of drug interactions increases with the number of medications; work with health care practitioners to eliminate unnecessary medications (Ansari 2010).

  MANAGEMENT OF COMMON DRUG-DRUG INTERACTIONS OBSERVED

    These drug-drug interactions should be managed in every patient. Special attention should be given to elderly because in those patients, not only major interactions but also the interactions with moderate potential should be given equal attention. Management measures for observed interactions can be seen in Table 5.

        Table 5: Severity and management of Common drug-drug interactions

Interacting Drugs	Incidence of Interaction		Severity	Potential Danger	Management
Aspirin↔clopidogrel			Major	Life-threatening bleeding	Avoid aspirin use in high risk patients
Spironolactone↔lisinopril			Major	Elevated serum potassium level	Regularly monitor renal function and serum potassium
Clopidogrel↔Omeprazole			Major	Antiplatelet activity of clopidogrel decrease	Use with caution if necessary. Ranitidine is safe alternative
Atorvastatin↔clopidogrel			Moderate	Platelet inhibition	No special precaution is needed
Atenolol↔aspirin Aspirin↔Bisoprolol Aspirin↔metoprolol			Moderate	B.P lowering effect of  β-blockers is reduced	Monitor B.P. change to low dose aspirin/ nonsalicylate antiplatelet agent/ other anti-hypertensive therapy
Aspirin↔lisinopril Aspirin↔perindopril Aspirin↔ramipril Aspirin↔captopril			Moderate	Hypotensive effect reduced	Monitor B.P and Haemodynamic Parameters
Glyburide↔Captopril			Moderate	Risk of Hypoglycemia may be increased	Carefully observe for the symptoms of hypoglycemia
Diltiazem↔Ranitidine			Moderate	Therapeutic & toxic effects of DILTIAZEM may be increased	Reduce DILTIAZEM dose if signs of toxicity appear
Furosemide↔acetaminop- Hen			Minor	Effect of loop diuretic (furosemide) decreased	No special precaution
Aspirin↔furosemide			Minor	Diuretic response impaired	No clinical interventions required. Use aspirin with caution.
Spironolactone↔aspirin			Minor	Spironolactone-induced natriuresis is blocked by aspirin	Monitor B.P. and serum sodium. Increasing spironolactone dose reverse effect of interaction.
Lisinopril↔furosemide			Minor	Effect of loop diuretic (furosemide) decreased	Monitor carefully fluid status or body weight of patients
Furosemide↔Glimepiride			Minor	Hyperglycemia	No clinical interventions necessary
Aspirin↔Omeprazole			Minor	Increase gastric adverse effect, reduce anti-platelet activity	Monitor for increase gastric adverse effect. Avoid concurrent use of these, as patients are at risk of serious gastric disorder

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   CONCLUSION

   This study report is done for educational purpose. This report tells about drug-drug interactions seen in cardiovascular patients. Those interactions are based on the patient characteristics i.e. age, gender, etc, comorbidities and number of drug taken by patients. This report also tells the common interactions in cardiovascular patients, their incidence of interaction and management measures. Aspirin and clopidogrel is the major interaction prescribing in all age group along with atorvastatin resulting in second most occurring interaction i.e. atorvastatin and clopidogrel. Moderate interactions are very common in elderly. As elderly has decreased renal and hepatic functions, these moderate type interactions work like the major in case of most elderly.

   Healthcare professional should work together to lessen or stop the incidence of interaction in the cardiovascular patients. Every healthcare professional should know about the most prevalent interaction. Healthcare professional and public should understand the role of pharmacist in hospital and community level. When pharmacist is the main part of prescription dispensing, thenthere will be less chance of Drug-drug interactions.

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